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We discuss basic properties and some applications of a generalized notion of differential for set-valued maps, called Quasi Differential Quotient. The latter was proved to be extremely useful to deal with several open questions in Optimal Control, such as the so called “Infimum Gap” problem. Furthermore, it recently revealed to be a valuable tool to prove second order necessary conditions expressed in terms of non-smooth Lie-brackets when the vector field is merely Lipschitz continuous. In this paper, we present a first step towards a more systematic theory of Quasi Differential Quotients and we study the relation between Quasi Differential Quotients and other generalized differentials such as the Sussmann’s Generalized Differential Quotient and Sussman’s Approximate Generalized Differential Quotient, the Clarke’s Generalized Jacobian and the Warga’s Derivative Container. [ABSTRACT FROM AUTHOR]

Summary: Cryptococcosis is an invasive mycosis caused mainly by Cryptococcus gattii and C. neoformans and is treated with amphotericin B (AMB), fluconazole and 5-fluorocytosine. However, antifungal resistance, limited and toxic antifungal arsenal stimulate the search for therapeutic strategies such as drug repurposing. Among the repurposed drugs studied, the selective serotonin reuptake inhibitors (SSRIs) have shown activity against Cryptococcus spp. However, little is known about the antifungal effect of duloxetine hydrochloride (DH), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), against C. neoformans and C. gattii. In this study, DH inhibited the growth of several C. neoformans and C. gattii strains at concentrations ranging from 15.62 to 62.50 µg/mL. In addition, DH exhibited fungicidal activity ranging from 15.62 to 250 µg/mL. In biofilm, DH treatment reduced Cryptococcus spp. biomass at a level comparable to AMB, with a significant reduction (85%) for C. neoformans biofilms. The metabolic activity of C. neoformans and C. gattii biofilms decreased significantly (99%) after treatment with DH. Scanning electron micrographs confirmed the anti-biofilm activity of DH, as isolated cells could be observed after treatment. In conclusion, DH showed promising antifungal activity against planktonic cells and biofilms of C. neoformans and C. gattii, opening perspectives for further studies with DH in vivo. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effectiveness of ozone therapy in guided bone regeneration (GBR) for critical size calvarial defects in rats. Materials and methods: 96 male Wistar rats were divided into four groups (n = 6 each). An 8 mm critical defect was created in the calvaria of each rat. The groups were: BIO (porcine collagen membrane, BioGide®), BIO + OZ (membrane with systemic ozone therapy every 2 days), COA + OZ (blood clot with ozone therapy), and COA (blood clot only). Evaluations at 7, 15, 30, and 60 days included histological, histomorphometric, inflammatory profile, Micro-CT, and immunohistochemical analyses. Statistical analysis involved two-factor ANOVA with Tukey’s post-hoc test for general data, and one-factor ANOVA with Holm-Sidak post-hoc test for Micro-CT data. Results: The BIO + OZ group demonstrated superior bone regeneration with well-organized, mature bone tissue and significant bone formation at 30 and 60 days. The COA + OZ group showed early angiogenesis and reduced inflammation, resulting in complete defect closure by 30 days. The BIO group had good regeneration, but less mature tissue compared to BIO + OZ. The COA group exhibited limited bone formation and higher porosity. Conclusion: Ozone therapy positively influences bone regeneration by enhancing cell proliferation and the healing response. Clinical relevance: Improving regenerative processes with auxiliary therapies like ozone therapy can be significant for advancing dental reconstructions. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review aims to explore the emerging potential of artificial intelligence (AI) in refining risk prediction, clinical diagnosis, and treatment stratification for cardiomyopathies, with a specific emphasis on arrhythmogenic cardiomyopathy (ACM). Recent Findings: Recent developments highlight the capacity of AI to construct sophisticated models that accurately distinguish affected from non-affected cardiomyopathy patients. These AI-driven approaches not only offer precision in risk prediction and diagnostics but also enable early identification of individuals at high risk of developing cardiomyopathy, even before symptoms occur. These models have the potential to utilise diverse clinical input datasets such as electrocardiogram recordings, cardiac imaging, and other multi-modal genetic and omics datasets. Summary: Despite their current underrepresentation in literature, ACM diagnosis and risk prediction are expected to greatly benefit from AI computational capabilities, as has been the case for other cardiomyopathies. As AI-based models improve, larger and more complicated datasets can be combined. These more complex integrated datasets with larger sample sizes will contribute to further pathophysiological insights, better disease recognition, risk prediction, and improved patient outcomes. [ABSTRACT FROM AUTHOR]

The variability in response to conventional prostate cancer (PC) therapies, coupled with the emergent issue of drug resistance, underscores the critical need for innovative treatment strategies. Aerobic physical exercise reduced incidence of several cancers, but the mechanism underlying these effects associated the nanoemulsion not fully understood. The application of a lipid nanoemulsion (LDE) delivery system for docetaxel (DTX), showing marked enhancement in therapeutic efficacy when combined with aerobic physical exercise. This novel intervention potentiates the antitumor activity of LDE-delivered DTX by augmenting nanoparticle internalization and inducing cell cycle arrest. Our findings reveal that this synergistic treatment not only significantly reduces prostate weight and mitigates adenocarcinoma proliferation but also attenuates anti-apoptotic BCL-2 protein expression. Concurrently, it elevates pro-apoptotic proteins and diminishes inflammatory markers. Metabolic profiling of the combined therapy group disclosed additional benefits, such as reduced lipid and plasma glucose levels. Collectively, our data illuminate the profound impact of integrating LDE-mediated DTX delivery with structured physical exercise, which together spearhead a dual-front assault on PC. This multimodal approach heralds a new paradigm in PC management, accentuating the promise of combined pharmacological and non-pharmacological interventions to elevate tumor suppressor protein activity and refine patient outcomes. [ABSTRACT FROM AUTHOR]

Kuznetsov and Polishchuk provided a general algorithm to construct exceptional collections of maximal length for homogeneous varieties of type A, B, C, D. We consider the case of the spinor tenfold and we prove that the corresponding collection is full, i.e. it generates the whole derived category of coherent sheaves. We also verify strongness and purity of such collection. As a step of the proof, we construct some resolutions of homogeneous vector bundles which might be of independent interest. [ABSTRACT FROM AUTHOR]

Type T Large Granular Lymphocyte Leukemia (T-LGLL) is a chronic disorder characterized by the abnormal proliferation of clonal cytotoxic T cells. The intriguing association of T-LGLL with autoimmune and inflammatory diseases, the most prominent example being rheumatoid arthritis, raises questions about the underlying pathophysiologic relationships between these disorders which share several biological and clinical features, most notably neutropenia, which is considered as a clinical hallmark. Recent progress in molecular genetics has contributed to a better understanding of pathogenetic mechanisms, thus moving our knowledge in the field of LGL leukemias forward. Focusing on the constitutive activation of STAT3 pathway and the well-established role of STAT3 mutations in T-LGLL, we herein discuss whether the T cell clones occurring in comorbid conditions are the cause or the consequence of the immune-inflammatory associated events. Overall, this review sheds light on the intricate relationships between inflammation and cancer, emphasizing the importance of the STAT3 gene and its activation in the pathophysiology of these conditions. Gaining a deeper understanding of these underlying mechanisms seeks to pave the way for the development of novel targeted therapies for patients affected by inflammation-related cancers. [ABSTRACT FROM AUTHOR]

We consider generalized homogeneous roofs, i.e. quotients of simply connected, semisimple Lie groups by a parabolic subgroup, which admit two projective bundle structures. Given a general hyperplane section on such a variety, we study the zero loci of its pushforwards along the projective bundle structures and we discuss their properties at the level of Hodge structures. In the case of the flag variety F(1,2,n) with its projections to ℙn− 1 and G(2,n), we construct a derived embedding of the relevant zero loci by methods based on the study of B-brane categories in the context of a gauged linear sigma model. [ABSTRACT FROM AUTHOR]

Endocrine disruptors (ED) are compounds dispersed in the environment that modify hormone biosynthesis, affecting hormone-dependent organs such as the prostate. Studies have only focused on evaluating the effects of ED alone or in small groups and short intervals and have not adequately portrayed human exposure. Therefore, we characterized the prostate histoarchitecture of rats exposed to an ED mixture (ED Mix) mimicking human exposure. Pregnant females of the Sprague–Dawley strain were randomly distributed into two experimental groups: Control group (vehicle: corn oil, by gavage) and ED Mix group: received 32.11 mg/kg/day of the ED mixture diluted in corn oil (2 ml/kg), by gavage, from gestational day 7 (DG7) to post-natal day 21 (DPN21). After weaning at DPN22, the male pups continued to receive the complete DE mixture until they were 220 days old when they were euthanized. The ED Mix decreased the epithelial compartment, increased the fractal dimension, and decreased glandular dilation. In addition, low-grade prostatic intraepithelial neoplasia was observed in addition to regions of epithelial atrophy in the group exposed to the ED Mix. Exposure to the mixture decreased both types I and III collagen area in the stroma. We concluded that the ED Mix was able to cause alterations in the prostatic histoarchitecture and induce the appearance of preneoplastic lesions. [ABSTRACT FROM AUTHOR]

With reference to an optimal control problem where the state has to approach asymptotically a closed target while paying a non-negative integral cost, we propose a generalization of the classical dissipative relation that defines a Control Lyapunov Function to a weaker differential inequality. The latter involves both the cost and the iterated Lie brackets of the vector fields in the dynamics up to a certain degree k ≥ 1 , and we call any of its (suitably defined) solutions a degree-kMinimum Restraint Function. We prove that the existence of a degree-k Minimum Restraint Function allows us to build a Lie-bracket-based feedback which sample stabilizes the system to the target while regulating (i.e., uniformly bounding) the cost. [ABSTRACT FROM AUTHOR]

Microenvironmental factors are known fundamental regulators of the phenotype and aggressiveness of glioblastoma (GBM), the most lethal brain tumor, characterized by fast progression and marked resistance to treatments. In this context, the extracellular matrix (ECM) is known to heavily influence the behavior of cancer cells from several origins, contributing to stem cell niches, influencing tumor invasiveness and response to chemotherapy, mediating survival signaling cascades, and modulating inflammatory cell recruitment. Here, we show that collagen VI (COL6), an ECM protein widely expressed in both normal and pathological tissues, has a distinctive distribution within the GBM mass, strongly correlated with the most aggressive and phenotypically immature cells. Our data demonstrate that COL6 sustains the stem-like properties of GBM cells and supports the maintenance of an aggressive transcriptional program promoting cancer cell proliferation and survival. In particular, we identified a specific subset of COL6-transcriptionally co-regulated genes, required for the response of cells to replicative stress and DNA damage, supporting the concept that COL6 is an essential stimulus for the activation of GBM cell response and resistance to chemotherapy, through the ATM/ATR axis. Altogether, these findings indicate that COL6 plays a pivotal role in GBM tumor biology, exerting a pleiotropic action across different GBM hallmarks, including phenotypic identity and gene transcription, as well as response to treatments, thus providing valuable information for the understanding of the complex microenvironmental cues underlying GBM malignancy. [ABSTRACT FROM AUTHOR]

Hepatitis Delta is a disease caused by exposure to hepatitis B (HBV) and hepatitis D (HDV) viruses, usually with a more severe clinical outcome when compared to an HBV monoinfection. To date, the real prevalence of HDV infection is underestimated and detection methods are poorly available, especially in more endemic regions. Therefore, a one-step RT-qPCR method for quantification of HDV-RNA was developed. Biological samples were selected between 2017 and 2023 from patients at the Ambulatório Especializado em Hepatites Virais of the Centro de Pesquisa em Medicina Tropical de Rondônia and Serviço de Assistência Especializada and underwent the test developed by this study and a second quantitative RT-qPCR assay. The slope of the initial quantitative assay was − 3.321 with an efficiency of 100.04% and amplification factor equal to 2. Analysis of the repeatability data revealed a Limit of Quantification of 5 copies/reaction and Limit of Detection (95%) of 2.83 copies per reaction. In the diagnostic sensitivity tests, there was an accuracy of 97.37% when compared to the reference test. This assay proved to be highly efficient and reproducible, making it a valuable tool to monitor hepatitis Delta patients and assess the risk of disease progression, as well as the effectiveness of treatment. [ABSTRACT FROM AUTHOR]

The successful operation of AGATA requires a complex mechanical support structure for the safe and reliable operation of the detectors. Three mechanical structures were designed for the scientific campaigns at LNL, GSI and GANIL, each accommodating an increasing number of detectors. The present phase of the project, to increase the number of detectors from 60 to 180 (the 4 π spectrometer), required a new concept in mechanical support. The detectors also require a suite of associated instrumentation, infrastructures and good system design for their optimum performance. This includes the automatic liquid nitrogen filling system, high and low voltage power supplies, and a series of signal cables and distribution systems. A well-designed electromagnetic compatibility across all the sub-systems is essential. An additional requirement is an easily accessible database that records the status of the wide range of components utilised on the project. This article describes all aspects of the mechanics and infrastructures. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading cause of death in the world and arterial hypertension (AH) accounts for 13.8% of deaths caused by cardiovascular diseases. Strength training interventions could be an important alternative tool for blood pressure control, however, consistent evidence and the most effective training protocol for this purpose are yet to be established. The current study used the Cochrane methodology to systematically review randomized controlled trials (RCTs) that investigated the effect of strength training on blood pressure in hypertensive patients. A systematic search was conducted in the PubMed, EMBASE, Scopus, Cochrane Library, and World Health Organization databases. This review included controlled trials that evaluated the effect of strength training for 8 weeks or more in adults with arterial hypertension, published up to December 2020. Data are described and reported as the weighted mean difference of systolic and diastolic pressure and a 95% confidence interval. Protocol registration: PROSPERO registration number CRD42020151269. A total of 14 studies were identified, including a combined total of 253 participants with hypertension. The meta-analysis showed that mean values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly after strength training interventions. The strongest effect of strength training on decreasing blood pressure was observed in protocols with a moderate to vigorous load intensity (> 60% of one-repetition maximum-1RM), a frequency of at least 2 times per week, and a minimum duration of 8 weeks. We concluded that strength training interventions can be used as a non-drug treatment for arterial hypertension, as they promote significant decreases in blood pressure. [ABSTRACT FROM AUTHOR]

Different harmful events affecting high voltage overhead lines (OHLs) cause changes in the mechanical tension (tensile strength) of conductors. A mechanical monitoring of OHLs, therefore, can provide useful additional information (compared with the information provided by the widely used SCADA systems) about the power system state. The tension measurements combined with a few environmental measurements (air temperature, wind speed) can be used for an automatic (fast) detection of different events and for their approximate location along an OHL, reducing the impact of these events. Referring to 132–150 kV sub-transmission OHLs, this paper proposes some original algorithms, based on the mechanical monitoring of OHLs, for the automatic detection of the following events: conductor breaking, fall of trees on the conductors, ice/snow sleeve accretion on the conductors, strands breaking and galloping. The proposed algorithms require a limited number of sensors placed along the OHLs for measurements of the conductor tension and weather-related quantities. [ABSTRACT FROM AUTHOR]

A great number of prediction methods have been proposed in the past several decades for residential building energy consumption prediction. In this paper, the proposed machine learning model allows the prediction of the cooling and heating system load of residential buildings. These loads in this study were modelled as functions of eight input variables such as relative compactness, surface area, wall area, roof area, overall height, orientation, glazing area, and glazing area distribution.The model is based on eXtreme Gradient Boosting (XGBoost) which hyperparameters are adaptively tuned with a modified Jaya algorithm. The results of the proposed modified Jaya algorithm outperform the results of nine optimization metaheuristics to tune the XGBoost model based on tenfold cross-validation when applied to energy performance forecasting of residential buildings. It was also seen that XGBoost model applied to case of heating load obtained RMSE, determination coefficient R2 and MAE equals to 0.381, 0.998, and 0.2781, respectively, while that to cooling load the values were 0.9757, 0.989, and 0.612, respectively. Consequently, the XGBoost combined with the modified Jaya can be a reasonable tool for forecasting energy due to high accuracy, effectiveness and stability. [ABSTRACT FROM AUTHOR]

This paper describes the development of a mechanism to deal with time windows constraints. To the best of our knowledge, the time windows constraints are difficult to be fulfilled even for state-of-the-art methods. Therefore, the main contribution of this paper is to propose a new computational technique to deal with such constraints. Such technique was tested combined with two metaheuristics to solve the discrete and dynamic Berth Allocation Problem. The technique ensures obtaining feasible solutions in terms of vessels time windows constraints, which are treated as hard constraints. A data set generator was created, resulting in a diversity of problems in terms of time windows constraints. A detailed computational analysis was carried out to compare the performance of both metaheuristics considering the technique. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutations in genes encoding desmosomal proteins. Variants in plakophilin-2 gene (PKP2) are the most common cause of the disease, associated with conventional ARVC phenotype. The study aims to evaluate the prevalence of PKP2 variants and examine genotype–phenotype correlation in Polish ARVC cohort. All 56 ARVC patients fulfilling the current criteria were screened for genetic variants in PKP2 using denaturing high-performance liquid chromatography or next-generation sequencing. The clinical evaluation involved medical history, electrocardiogram, echocardiography, and follow-up. Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. All truncating variants are classified as pathogenic/likely pathogenic, while the missense variant is classified as variant of uncertain significance. Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1–V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) and left ventricular damage progression (p = 0.04). Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). Pathogenic variants in PKP2 are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis. ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. Combined endpoint of death or heart transplant was less frequent in this group. [ABSTRACT FROM AUTHOR]

Dorado is a nearby (17.69 Mpc) strongly evolving galaxy group in the Southern Hemisphere. We are investigating the star formation in this group. This paper provides a FUV imaging of NGC 1533, IC 2038 and IC 2039, which form a substructure, south west of the Dorado group barycentre. FUV CaF2-1 UVIT-Astrosat images enrich our knowledge of the system provided by GALEX. In conjunction with deep optical wide-field, narrow-band H α and 21-cm radio images we search for signatures of the interaction mechanisms looking in the FUV morphologies and derive the star formation rate. The shape of the FUV luminosity profile suggests the presence of a disk in all three galaxies. FUV emission is detected out to the optical size for IC 2038, and in compact structures corresponding to H α and H ii bright features in NGC 1533. A faint FUV emission, without an optical counterpart, reminiscent of the H i structure that surrounds the outskirts of NGC 1533 and extends up to IC 2038/2039, is revealed above the local background noise. [ABSTRACT FROM AUTHOR]

The RAD51 recombinase plays critical roles in safeguarding genome integrity, which is fundamentally important for all living cells. While interphase functions of RAD51 in maintaining genome stability are well-characterised, its role in mitosis remains contentious. In this study, we show that RAD51 protects under-replicated DNA in mitotic human cells and, in this way, promotes mitotic DNA synthesis (MiDAS) and successful chromosome segregation. In cells experiencing mild replication stress, MiDAS was detected irrespective of mitotically generated DNA damage. MiDAS broadly required de novo RAD51 recruitment to single-stranded DNA, which was supported by the phosphorylation of RAD51 by the key mitotic regulator Polo-like kinase 1. Importantly, acute inhibition of MiDAS delayed anaphase onset and induced centromere fragility, suggesting a mechanism that prevents the satisfaction of the spindle assembly checkpoint while chromosomal replication remains incomplete. This study hence identifies an unexpected function of RAD51 in promoting genomic stability in mitosis. RAD51 is a well known player of DNA repair and homologous recombination. Here the authors reveal a function for RAD51 in protecting under-replicated DNA in mitotic human cells, promoting mitotic DNA synthesis (MiDAS) and successful chromosome segregation. [ABSTRACT FROM AUTHOR]

Interventions that can modulate subcutaneous white adipose tissue (scWAT) function, such as exercise training and nutritional components, like taurine, modulate the inflammatory process, therefore, may represent strategies for obesity treatment. We investigated the effects of taurine supplementation in conjunction with exercise on inflammatory and oxidative stress markers in plasma and scWAT of obese women. Sixteen obese women were randomized into two groups: Taurine supplementation group (Tau, n = 8) and Taurine supplementation + exercise group (Tau + Exe, n = 8). The intervention was composed of daily taurine supplementation (3 g) and exercise training for 8 weeks. Anthropometry, body fat composition, and markers of inflammatory and oxidative stress were determined in plasma and scWAT biopsy samples before and after the intervention. We found that, although taurine supplementation increased taurine plasma levels, no changes were observed for the anthropometric characteristics. However, Tau alone decreased interleukin-6 (IL-6), and in conjunction with exercise (Tau + Exe), increased anti-inflammatory interleukins (IL-15 and IL10), followed by reduced IL1β gene expression in the scWAT of obese women. Tau and Tau + Exe groups presented reduced adipocyte size and increased connective tissue and multilocular droplets. In conclusion, taurine supplementation in conjunction with exercise modulated levels of inflammatory markers in plasma and scWAT, and improved scWAT plasticity in obese women, promoting protection against obesity-induced inflammation. TRN NCT04279600 retrospectively registered on August 18, 2019. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients with this syndrome present SCN1A pathogenic variants, which encodes an alpha subunit of a neural voltage-dependent sodium channel. There is a correlation between PCDH19 pathogenic variants, encodes the protocadherin 19, and a similar disease to DS known as DS-like phenotype. The present review aims to clarify the differences between DS and DS-like phenotype according to the SCN1A and PCDH19 variants. A systematic review was conducted in PubMed and Virtual Health Library (VHL) databases, using "Dravet Syndrome" and "Severe Myoclonic Epilepsy in Infancy (SMEI)" search words, selecting cohort of studies published in journal with impact factor of two or greater. The systematic review was according to the Preferred Reporting Items for Systematic Review and Meta-Analysis recommendations. Nineteen studies were included in the present review, and a significant proportion of patients with DS-carrying SCN1A was greater than patients with DS-like phenotype-harboring PCDH19 variants (76.6% versus 23.4%). When clinical and genetic data were correlated, autism was predominantly observed in patients with DS-like-carrying PCDH19 variants compared to SCN1A variant carriers (62.5% versus 37.5%, respectively, P-value = 0.044, P-value corrected = 0.198). In addition, it was noticed a significant predisposition to hyperthermia during epilepsy crisis in individuals carrying PCDH19 variants (P-value = 0.003; P-value corrected = 0.027). The present review is the first to point out differences between the DS and DS-like phenotype according to the SCN1A and PCDH19 variants. [ABSTRACT FROM AUTHOR]

Background: In the absence of medical treatment and vaccination, individual behaviours are key to curbing the spread of COVID-19. Here we describe efforts to collect attitudinal and behavioural data and disseminate insights to increase situational awareness and inform interventions. Methods: We developed a rapid data collection and monitoring system based on a cross-national online survey, the "COVID-19 Health Behavior Survey". Respondent recruitment occurred via targeted Facebook advertisements in Belgium, France, Germany, Italy, the Netherlands, Spain, the United Kingdom, and the United States. We investigated how the threat perceptions of COVID-19, the confidence in the preparedness of organisations to deal with the pandemic, and the adoption of preventive and social distancing behaviours are associated with respondents' demographic characteristics. Results: We analysed 71,612 questionnaires collected between March 13-April 19, 2020. We found substantial spatio-temporal heterogeneity across countries at different stages of the pandemic and with different control strategies in place. Respondents rapidly adopted the use of face masks when they were not yet mandatory. We observed a clear pattern in threat perceptions, sharply increasing from a personal level to national and global levels. Although personal threat perceptions were comparatively low, all respondents significantly increased hand hygiene. We found gender-specific patterns: women showed higher threat perceptions, lower confidence in the healthcare system, and were more likely to adopt preventive behaviours. Finally, we also found that older people perceived higher threat to themselves, while all respondents were strongly concerned about their family. Conclusions: Rapid population surveys conducted via Facebook allow us to monitor behavioural changes, adoption of protective measures, and compliance with recommended practices. As the pandemic progresses and new waves of infections are a threatening reality, timely insights from behavioural and attitudinal data are crucial to guide the decision-making process. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. Defective complex III is associated with a highly variable clinical spectrum. We show that pyocyanin, a bacterial redox cycler, can replace the redox functions of complex III, acting as an electron shunt. Sub-μM pyocyanin was harmless, restored respiration and increased ATP production in fibroblasts from five patients harboring pathogenic mutations in TTC19, BCS1L or LYRM7, involved in assembly/stabilization of complex III. Pyocyanin normalized the mitochondrial membrane potential, and mildly increased ROS production and biogenesis. These in vitro effects were confirmed in both DrosophilaTTC19KO and in Danio rerioTTC19KD, as administration of low concentrations of pyocyanin significantly ameliorated movement proficiency. Importantly, daily administration of pyocyanin for two months was not toxic in control mice. Our results point to utilization of redox cyclers for therapy of complex III disorders. Mitochondrial diseases, including those caused by defects in complex III of the respiratory chain, lack curative treatments. Here the authors report that the small molecule pyocyanin has beneficial effects in cells derived from patients with complex III-deficiency as well as in fly and zebrafish genetic models with reduced complex III activity. [ABSTRACT FROM AUTHOR]

The high-fat diet (HFD) stimulates an increase in lipids and can be prejudicial for harmful to prostatic morphogenesis. Polyunsaturated fatty acid (PUFAs) have anti-inflammatory and antioxidant action in some types of cancer. The combination of aerobic physical exercise and PUFA can be more effective and reduce the risk of death. The study evaluates the effects of aerobic physical exercise associated with omega-3 (fish and chia oils), on the ventral prostate of Wistar rats those fed with HFD. Here, we report that HFD modified the final body weight and the weight gain, decreased the expression of the androgen receptor and increased prostatic inflammation via TNF-α produced damage prostatic like intraepithelial neoplasia. The supplementation with fish oil decreases final body weight, reduced BCL-2 and inflammation compared to chia oil; aerobic physical exercise associated with fish oil reduced lipids circulant and prostatic, increased proteins pro-apoptotic expression and reduced IL-6 (p < 0.0001) and TNF-α potentiating the CAT (p = 0.03) and SOD-1 (p = 0.001) expression. Additionally, the chia oil increased the NRF-2 (p < 0.0001) and GSS (p = 0.4) genes. PUFAs reduced the damage caused by excessive high-fat diet in the prostate so that there is greater effectiveness in omega-3 intake, it is necessary to associate with aerobic physical exercise. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has spread rapidly around the world, with Brazil currently considered an epicenter of the pandemic. The Northern region has the second highest incidence coefficient, as well as the third highest mortality rate in the country. This study aimed to investigate information about the evolutionary history of epidemic spread and genetic aspects of strains isolated on the Western Amazon, in the State of Rondônia, Brazil. It was possible to detect a total of 22 mutations. Some of these alterations may possibly be related to effects on transmissibility, the fidelity of RNA replication, the ability of cancer patients to respond to infection, beyond a mutation that emerged after the introduction of SARS-CoV-2 in Rondônia. At least two events of introduction were detected, corresponding to the B.1 and B.1.1 European lineages. An introduction was observed possibly through Argentina, where strains originated that circulated in the Minas Gerais and Ceará Brazilian states, prior to Rondônia (B.1.), as well as through the Minas Gerais state and the Federal District, which gave rise to strains that spread to Rondônia, from the capital to more rural parts of the state (B.1.1.). The findings show the need to monitor the genetic epidemiology of COVID-19, in order to surveil the virus's evolution, dispersion and diversity. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effects of different doses of 2,4-dichlorophenoxyacetic herbicide in rat hearts. Exposure was through rat food that was nebulized with the herbicide. Thirty adult male Wistar rats (200–300 g) were used. The diet was exposed to 2,4-D in two different doses (CG: control group 10 ml distilled water; LCG: low concentration group 3.71 × 10−3 g.ia/ha diluted in 10 ml saline at 0.9% and HCG: High concentration group 9.28 × 10−3 g.ia/ha diluted in 10 ml 0.9% saline). After 6 months of exposure, blood samples were collected for CKMB evaluation, and left ventricular fragments were analyzed by histological evaluation, fibrosis measurements, fractal dimension and immunohistochemistry (BAX, Bcl2, TNF-α and NF-kB). There were no significant changes in CK-MB concentration, histological parameters, fibrosis measurements and fractal dimension. Long-term oral consumption of food nebulized by the herbicide 2,4-D promoted an increase in BAX, Bcl-2/BAX, and cytoplasmic NF-kB in the nuclear area of the group that received the highest dose of the herbicide. This suggests that the herbicide induces cardiotoxicity. [ABSTRACT FROM AUTHOR]

Our aim is to evaluate the effects of high-fat diet and strength training on ventral prostate health through investigations of rat prostate histology, endocrine modulation, and the expression of proliferative and apoptotic marker, including androgen receptors (AR), glucocorticoid receptors (GR), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (BAX), Fas cell surface death receptor (Fas/CD95/Apo-1), and Nuclear Factor Kappa-B (NF-κB). Eighty Wistar rats were into one of four subgroups: control (CT), strength training (ST), high-fat diet consumption (HF), and high-fat diet consumption with strength training (HFT). Animals then underwent strength training and/or high-fat diet consumption for 8 or 12 weeks, after which animals were euthanized and markers of prostatic health were evaluated histologically and through immunolabeling. Our results indicate that physical strength training reduced the expression of the prostate cell proliferation marker Bcl-2 while increasing expression of the pro-apoptotic marker BAX, as well as increasing expression of AR and GR relevant in the Bcl-2 pathway. We conclude that a high-fat diet can alter hormone receptor levels and cell-cycle protein expression, thereby modifying prostatic homeostasis, and that strength training was able to reduce prostate damage induced by high-fat diet consumption. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prevalence of two recurrent somatic mutations (−124 C>T and −146 C>T) within the promoter of the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs). Methods: We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs. Results: Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with −124 C>T and −146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p = 0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival. Conclusion: TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome. [ABSTRACT FROM AUTHOR]

Road traffic contributes to atmospheric particulate matter with exhaust (fuel combustion) and non-exhaust (wear of vehicle parts such as brake, tires and abrasion of the road surface) emissions. Road dust is composed of particles belonging to natural and anthropogenic sources related in large part to road traffic. To date, understanding the relative contribution of road dust resuspension and particles directly emitted by abrasion to particulate matter is still a matter of debate. In this work, road dust and resuspended particles samples are collected at different heights and with increasing sampling time near a busy road of Venice mainland. Elemental composition and morphology of particles were investigated with a combination of techniques: inductively coupled plasma optical emission spectroscopy (ICP-OES), inductively coupled plasma mass spectrometry (ICP-MS), laser diffraction analysis and scanning electron microscopy–energy-dispersive X-ray spectrometry (SEM–EDX). The differences between deposited and resuspended particles were highlighted and the main pollutant sources were identified to study the resuspension process related to the traffic flow. Resuspended particles were divided into six groups related to the presence of anti-ice material, to soil resuspension and to the road surface and vehicle parts wear. The contributions of clustered particles vary with the height from the road level. This study, the first one focusing on the road traffic particles resuspension in Veneto region, will provide topical information for the identification of this source in atmospheric particulate samples. [ABSTRACT FROM AUTHOR]

Butyltin compound (BTC) contamination was evaluated in two north Adriatic marinas, San Rocco (Italy) and Lucija (Slovenia). BTC sedimentary concentrations (121 ± 46 and 352 ± 30 ng Sn g−1 in San Rocco and Lucija, respectively) evidenced the past use of antifouling paints, confirmed by the reduced tributyltin content (~ 46%) with respect to the sum of BTC. Elemental and organic carbon isotopic (δ13C) analyses of bulk sediments and its lipid and humic substances were performed in order to evaluate their role in BTC partitioning and preservation. The δ13C of sedimentary bulk and refractory organic matter suggested that diagenetic processes could play a role in the preservation or release of pollutants. No contamination was found in water collected from the benthic chamber and thus, fluxes at the sediment-water interface were not assessed, except for MBT efflux at Lucija (28.9 ng Sn m−2 day−1). Nevertheless, BTC concentrations in porewaters (up to 75 ng Sn l−1) and rather low sediment-porewater partitioning coefficients (Kd) with respect to the data reported in the literature would suggest a potential risk of the reintroduction of BTC into the water column at both sites: at Lucija, sedimentary contamination is high despite the greater Log Kd, whilst at San Rocco, the low BTC concentration is associated with a reduced sediment affinity. [ABSTRACT FROM AUTHOR]

Silica nanoparticles (NPs) are versatile nanomaterials, which are safe with respect to biomedical applications, and therefore are highly investigated. The advantages of NPs include their ease of preparation, inexpensive starting materials and the possibility of functionalization or loading with various doping agents. However, the solubility of the doping agent(s) imposes constraints on the choice of the reaction system and hence limits the range of molecules that can be included in the interior of NPs. To overcome this problem, herein, we improved the current state of the art synthetic strategy based on Pluronic F127 by enabling the synthesis in the presence of large amounts of organic solvents. The new method enables the preparation of nanoparticles doped with large amounts of water-insoluble doping agents. To illustrate the applicability of the technology, we successfully incorporated a range of phosphorescent metalloporphyrins into the interior of NPs. The resulting phosphorescent nanoparticles may exhibit potential for biological oxygen sensing. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses (MPS) are a subgroup of 11 monogenic lysosomal storage disorders due to the deficit of activity of the lysosomal hydrolases deputed to the degradation of mucopolysaccharides. Although individually rare, all together they account for at least 1:25,000 live births. In this study, we present the genetic analysis of a population of 71 MPS patients enrolled in a multicenter Italian study. We re-annotated all variants, according to the latest recommendations, and re-classified them as suggested by the American College of Medical Genetics and Genomics. Variant distribution per type was mainly represented by missense mutations. Overall, 10 patients had received no molecular diagnosis, although 6 of them had undergone either HSCT or ERT, based on clinical and enzymatic evaluations. Moreover, nine novel variants are reported.Conclusions: Our analysis underlines the need to complete the molecular diagnosis in patients previously diagnosed only on a biochemical basis, suggests a periodical re-annotation of the variants and solicits their deposition in public databases freely available to clinicians and researchers. We strongly recommend a molecular diagnosis based on the analysis of the "trio" instead of the sole proband. These recommendations will help to obtain a complete and correct diagnosis of mucopolysaccharidosis, rendering also possible genetic counseling. What is known • MPS are a group of 11 metabolic genetic disorders due to deficits of enzymes involved in the mucopolysaccharides degradation. • Molecular analysis is commonly performed to confirm enzymatic assays. What is new • Eighty-six percent of the 71 patients we collected received a molecular diagnosis; among them, 9 novel variants were reported. • We stress the importance of molecular diagnosis in biochemically diagnosed patients, encourage a periodical re-annotation of variants according to the recent nomenclature and their publication in open databases. [ABSTRACT FROM AUTHOR]

Cell junctions play an important role in coordinating intercellular communication and intracellular ultrastructures, with desmosomes representing the mechanical component of such intercellular connections. Mutations to desmosomal component proteins compromise both inter- and intracellular signalling and correlate with severe diseases like arrhythmogenic cardiomyopathy (AC), with pathological phenotypes in tissues subjected to intense mechanical stimuli (skin and heart). Here, we explore the consequences of dysfunctional desmosomes in one line of induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) derived from an AC patient with a homozygous pathogenic mutation in desmosomal component protein plakophilin-2 (PKP2). We specifically aim at investigating the response to mechanical stress in an AC-pathological setting. To this aim, we aligned hiPS-CMs on stretchable patterned substrates to mimic the cardiac functional syncytium and compared transcriptomic profiles of PKP2-mutated hiPS-CMs and healthy controls. AC-CMs display altered transcription towards a pro-fibrotic gene expression program, and concurrent dysregulation of gene sets closely associated with cell-to-cell connections. By integrating the culture substrate with a macroscopic stretching setup able to accurately apply cyclic uniaxial elongation, we show how response to mechanical loads in AC-CMs deviates from the canonical mechanical-stress response observed in healthy-CMs. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that oxidative and nitrosative stress (O&NS) pathways play a key role in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, only a handful of studies have directly compared alterations in O&NS pathways among patients with MDD and BD types I (BPI) and BPII. Thus, the current study compared superoxide dismutase (SOD1), lipid hydroperoxides (LOOH), catalase, nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) between mood disorder patients in a clinically remitted state. To this end 45, 23, and 37 participants with BPI, BPII, and MDD, respectively, as well as 54 healthy controls (HCs) were recruited. Z-unit weighted composite scores were computed as indices of reactive oxygen species (ROS) production and nitro-oxidative stress driving lipid or protein oxidation. SOD1, NOx, and MDA were significantly higher in MDD than in the other three groups. AOPP was significantly higher in BPI than in HCs and BPII patients. BPII patients showed lower SOD1 compared to all other groups. Furthermore, MDD was characterized by increased indices of ROS and lipid hydroperoxide production compared to BPI and BPII groups. Indices of nitro-oxidative stress coupled with aldehyde production or protein oxidation were significantly different among the three patient groups (BDII > BDI > MDD). Finally, depressive symptom scores were significantly associated with higher LOOH and AOPP levels. In conclusion, depression is accompanied by increased ROS production, which is insufficiently dampened by catalase activity, thereby increasing nitro-oxidative damage to lipids and aldehyde production. Increased protein oxidation with formation of AOPP appeared to be hallmark of MDD and BPI. In addition, patients with BPII may have protection against the damaging effects of ROS including lipid peroxidation and aldehyde formation. This study suggests that biomarkers related to O&NS could aid in the differentiation of MDD, BPI, and BPII. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that nitro-oxidative pathways play an important role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD) and maybe anxiety disorders. The current study aims to examine superoxide dismutase (SOD1), catalase, lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), malondialdehyde (MDA), glutathione (GSH), paraoxonase 1 (PON1), high-density lipoprotein cholesterol (HDL), and uric acid (UA) in participants with and without generalized anxiety disorder (GAD) co-occurring or not with BD, MDD, or tobacco use disorder. Z unit-weighted composite scores were computed as indices of nitro-oxidative stress driving lipid and protein oxidation. SOD1, LOOH, NOx, and uric acid were significantly higher and HDL and PON1 significantly lower in participants with GAD than in those without GAD. GAD was more adequately predicted by increased SOD + LOOH + NOx and lowered HDL + PON1 composite scores. Composite scores of nitro-oxidative stress coupled with aldehyde and AOPP production were significantly increased in participants with comorbid GAD + MDD as compared with all other study groups, namely MDD, GAD + BD, BD, GAD, and healthy controls. In conclusion, GAD is characterized by increased nitro-oxidative stress and lipid peroxidation and lowered lipid-associated antioxidant defenses, while increased uric acid levels in GAD may protect against aldehyde production and protein oxidation. This study suggests that increased nitro-oxidative stress and especially increased SOD1 activity, NO production, and lipid peroxidation as well as lowered HDL-cholesterol and PON1 activity could be novel drug targets for GAD especially when comorbid with MDD. [ABSTRACT FROM AUTHOR]

Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways. This present study examined the associations among chronic apical periodontitis (CAP), root canal endotoxin levels (lipopolysaccharides, LPS), O&NS pathways, depressive symptoms, and quality of life. Measurements included advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), lipid peroxides (LOOH), −sulfhydryl (SH) groups, total radical trapping antioxidant parameter (TRAP), and paraoxonase (PON)1 activity in participants with CAP, with and without depression, as well as healthy controls (no depression, no CAP). Root canal LPS levels were positively associated with CAP, clinical depression, severity of depression (as measured with the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory) and O&NS biomarkers, especially NOx and TRAP. CAP-related depression was accompanied by increased levels of NOx, LOOH, AOPP, and TRAP. In CAP participants, there was a strong correlation (r = 0.734, p < 0.001) between root canal LPS and the HDRS score. There were significant and positive associations between CAP or root canal endotoxin with the vegetative and physio-somatic symptoms of the HDRS as well as a significant inverse association between root canal endotoxin and quality of life with strong effects on psychological, environmental, and social domains. It is concluded that increased root canal LPS accompanying CAP may cause depression and a lowered quality of life, which may be partly explained by activated O&NS pathways, especially NOx thereby enhancing hypernitrosylation and thus neuroprogressive processes. Dental health and “leaky teeth” may be intimately linked to the etiology and course of depression, while significantly impacting quality of life. [ABSTRACT FROM AUTHOR]

Background: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.Methods: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.Results: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.Conclusions: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy. [ABSTRACT FROM AUTHOR]

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome.Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT=T0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4-8 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR.Results: Plasma levels of TERT were significantly lower at T2 (P<0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73-0.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10-4.11)-fold and 4.55 (95% CI 1.48-13.95)-fold higher, respectively, than those with undetectable plasma TERT levels.Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy. [ABSTRACT FROM AUTHOR]